Solid phase synthesis of chemical libraries

Abstract

The present invention provides compounds and compound libraries that are useful as protease modulators. The compounds and compound libraries are preferably made using the methods of the present invention which utilize peptide synthesis and combinatorial chemistry methods on a solid phase.

What is claimed is:  
     
         1 . A combinatorial library comprising compounds of the formula: 
       -P 1 —(P 2 ) y —P 4   I wherein:    P 1  is an arginine surrogate attached directly to a solid support;    P 2  is an amino acid residue;    y is an integer from 1 to about 12 wherein each P 2  can be the same or different; and    P 4  is a member selected from the group consisting of R—, RC(O)—, RR 1 NC(O)—, RSO 2 —, RR 1 N—SO 2 —, RS(O)—, RR 1 N—S(O)— and ROC(O)—, wherein R and R 1  are each independently selected from the group consisting of hydrogen, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted arylalkyl group, an optionally substituted heteroarylalkyl group, an optionally substituted heteroarylaryl group, an optionally substituted cycloalkyl group, an optionally substituted alkoxy group and an optionally substituted alkyl group.    
     
     
         2 . The combinatorial library of  claim 1 , wherein  
       
         
           
           
               
               
           
         
       
       is said arginine surrogate attached directly to said solid support having the formula:  
       
         
           
           
               
               
           
         
       
       wherein the ring ‘A’ is a member selected from the group consisting of a five- or a six-membered optionally substituted cycloalkyl group, optionally substituted aryl group and an optionally substituted heteroaryl group, wherein said heteroaryl group has from 1 to 3 heteroatoms selected from the group consisting of optionally substituted N, O, and S; and 
 z is 0 or 1;  
 L is selected from the group consisting of alkylene optionally interrupted by a heteroatom and S; and  
 t is 0 or 1.  
 
     
     
         3 . The combinatorial library of  claim 2 , wherein  
       
         
           
           
               
               
           
         
         is said arginine surrogate attached directly to said solid support having the formula:  
         
           
             
             
                 
                 
             
           
         
         wherein X is a heteroatom selected from the group consisting of optionally substituted N, S and O.  
       
     
     
         4 . The combinatorial library of  claim 1 , wherein each P 2  is an amino acid residue independently selected from the group consisting of an L-amino acid, a D-amino acid, sarcosine (Sar), norvaline (Nval), β-alanine (β-Ala), methionine sulfone (Met(O 2 ), cyclohexyl-glycine (chx-Gly), tetrahydro-3-isoquinolinecarboxylic acid (Tic), phenylglycine (phGly), 4-bromophenylalanine (4BrPhe), 3-fluorophenylalanine (3FPhe), and D-O-benzylserine Ser(Bz).  
     
     
         5 . The combinatorial library of  claim 2 , wherein  
       
         
           
           
               
               
           
         
       
       has the formula  
       
         
           
           
               
               
           
         
         wherein the ring ‘A’ is a member selected from the group consisting of a five- or a six-membered optionally substituted cycloalkyl group, optionally substituted aryl group and an optionally substituted heteroaryl group, wherein said heteroaryl group has from 1 to 3 heteroatoms selected from the group consisting of optionally substituted N, O, and S.  
       
     
     
         6 . The combinatorial library of  claim 5 , wherein said solid support is derived from a member selected from the group consisting of 4-nitrophenyl carbonate resin, imidazole carbonate resin and succinimidyl carbonate resin.  
     
     
         7 . The combinatorial library of  claim 5 , wherein  
       
         
           
           
               
               
           
         
       
       has the formula  
       
         
           
           
               
               
           
         
         wherein:  
         X is a heteroatom selected from the group consisting of S, O and optionally substituted N.  
       
     
     
         8 . The combinatorial library of  claim 3 , wherein said compounds have the formula:  
       
         
           
           
               
               
           
         
         wherein:  
         X is a heteroatom selected from the group consisting of optionally substituted N, S and O;  
         each P 2  may be the same or a different amino acid residue;  
         y is an integer of 1 to about 3;  
         G is carbon and n is 1; or alternatively,  
         G is sulfur and n is 0, 1 or 2;  
         Y is a heteroatom selected from the group consisting of optionally substituted N and O;  
         m is 0 or 1; and  
         R 4  is an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted arylalkyl group, an optionally substituted heteroarylalkyl group and an optionally substituted alkyl group.  
       
     
     
         9 . A combinatorial library comprising compounds of the formula: 
       P 1 —(P 2 ) y —P 4   Ia wherein:    P 1  is an arginine surrogate;    P 2  is an amino acid residue;    y is an integer from 1 to about 12 wherein each P 2  can be the same or different; and    P 4  is a member selected from the group consisting of R—, RC(O)—, RR 1 NC(O)—, RSO 2 —, RR 1 N—SO 2 —, RS(O)—, RR 1 N—S(O)— and ROC(O)—, wherein R and R 1  are each independently selected from the group consisting of hydrogen, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted arylalkyl group, an optionally substituted heteroarylalkyl group, an optionally substituted heteroarylaryl group, an optionally substituted cycloalkyl group, an optionally substituted alkoxy group and an optionally substituted alkyl group.    
     
     
         10 . The combinatorial library of  claim 9 , wherein the compounds have the formula  
       
         
           
           
               
               
           
         
         wherein the ring ‘A’ is a member selected from the group consisting of a five- or a six-membered optionally substituted cycloalkyl group, optionally substituted aryl group and an optionally substituted heteroaryl group, wherein said heteroaryl group has from 1 to 3 heteroatoms selected from the group consisting of optionally substituted N, O, and S; and  
         z is 0 or 1;  
         L is selected from the group consisting of alkylene optionally interrupted by a heteroatom and S;  
         t is 0 or 1;  
         q is an integer from 0 to about 3; and  
         y is an integer from 1 to about 12 wherein each P 2  can be the same or different.  
       
     
     
         11 . The combinatorial library of  claim 9 , wherein the compounds have the formula  
       
         
           
           
               
               
           
         
         wherein:  
         X is a heteroatom selected from the group consisting of N, S and O;  
         each P 2  may be the same or a different amino acid residue;  
         y is an integer of 1 to about 3;  
         G is carbon and n is 1; or alternatively,  
         G is sulfur and n is 0, 1 or 2;  
         Y is a heteroatom selected from the group consisting of optionally substituted N and O;  
         m is 0 or 1; and  
         R 4  is an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted arylalkyl group, an optionally substituted heteroarylalkyl group or an optionally substituted alkyl group.  
       
     
     
         12 . The combinatorial library of  claim 9 , wherein each P 2  is an amino acid residue independently selected from the group consisting of an L-amino acid, a D-amino acid, sarcosine (Sar), norvaline (Nval), β-alanine (β-Ala), methionine sulfone (Met(O 2 ), cyclohexyl-glycine (chx-Gly), tetrahydro-3-isoquinolinecarboxylic acid (Tic), phenylglycine (phGly), 4-bromophenylalanine (4BrPhe), 3-fluorophenylalanine (3FPhe), and D-O-benzylserine Ser(Bz).  
     
     
         13 . A method for preparing a protease modulator having an arginine surrogate on a solid support, said method comprising: 
 (a) attaching a protected arginine surrogate to said solid support to provide a protected support-bound arginine surrogate;    (b) deprotecting said support-bound arginine surrogate to form a deprotected support-bound arginine surrogate;    (c) contacting said deprotected support-bound arginine surrogate with at least one protected amino acid under conditions to provide a protected support-bound substituted arginine surrogate;    (d) deprotecting said protected support-bound substituted arginine surrogate to form a deprotected substituted support-bound arginine surrogate; and    (e) contacting said deprotected support-bound substituted arginine surrogate with at least one capping agent under conditions to provide a protease modulator having an arginine surrogate on said solid support.    
     
     
         14 . The method for preparing a protease modulator of  claim 13 , further comprising repeating step (c) and step (d) in iterative fashion with about 2 to about 12 protected amino acids.  
     
     
         15 . The method for preparing a protease modulator of  claim 13 , further comprising: 
 (f) removing said protease modulator having an arginine surrogate from said solid support.    
     
     
         16 . The method for preparing a protease modulator of  claim 13 , wherein said protected arginine surrogate has the formula:  
       
         
           
           
               
               
           
         
         wherein:  
         X is a heteroatom selected from the group consisting of N, S and O; and  
         PG is a protecting group.  
       
     
     
         17 . The method for preparing a protease modulator of  claim 16 , wherein said PG is a member selected from the group consisting of Fmoc, Alloc and Teoc.  
     
     
         18 . The method for preparing a protease modulator of  claim 13 , wherein said protected amino acid is an Fmoc protected amino acid.  
     
     
         19 . The method for preparing a protease modulator of  claim 18 , wherein the amino acid of said Fmoc protected amino acid is a member selected from the group consisting of an L-amino acid, a D-amino acid, sarcosine (Sar), norvaline (Nval), β-alanine (β-Ala), methionine sulfone (Met(O 2 ), cyclohexyl-glycine (chx-Gly), tetrahydro-3-isoquinolinecarboxylic acid (Tic), phenylglycine (phGly), 4-bromophenylalanine (4BrPhe), 3-fluorophenylalanine (3FPhe), and D-O-benzylserine Ser(Bz).  
     
     
         20 . The method for preparing a protease modulator of  claim 13 , wherein said capping agent is a member selected from the group consisting of R—, RC(O)—, RR 1 NC(O)—, RSO 2 —, RR 1 N—SO 2 —, RS(O)—, RR 1 N—S(O)— and ROC(O)—, wherein R and R 1  are each independently selected from the group consisting of hydrogen, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted arylalkyl group, an optionally substituted heteroarylalkyl group and an optionally substituted alkyl group.  
     
     
         21 . The method for preparing a protease modulator of  claim 13 , wherein said solid support is derived from a member selected from the group consisting of 4-nitrophenyl carbonate resin, imidazole carbonate resin and succinimidyl carbonate resin.  
     
     
         22 . The method for preparing a protease modulator of  claim 13 , wherein said protease modulator having an arginine surrogate on said solid support has the formula: 
       -P 1 —(P 2 ) y —P 4   I wherein:    P 1  is an arginine surrogate attached directly to a solid support;    P 2  is an amino acid residue;    y is an integer from 1 to about 12 wherein each P 2  can be the same or different; and    P 4  is a member selected from the group consisting of R—, RC(O)—, RR 1 NC(O)—, RSO 2 —, RR 1 N—SO 2 —, RS(O)—, RR 1 N—S(O)— and ROC(O)—, wherein R and R 1  are each independently selected from the group consisting of hydrogen, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted arylalkyl group, an optionally substituted heteroarylalkyl group, an optionally substituted heteroarylaryl group, an optionally substituted cycloalkyl group, an optionally substituted alkoxy group and an optionally substituted alkyl group.    
     
     
         23 . A protease modulator having the formula: 
       P 1 —(P 2 ) y —P 4   Ia wherein:    P 1  is an arginine surrogate;    P 2  is an amino acid residue;    y is an integer from 1 to about 12 wherein each P 2  can be the same or different; and    P 4  is a member selected from the group consisting of R—, RC(O)—, RR 1 NC(O)—, RSO 2 —, RR 1 N—SO 2 —, RS(O)—, RR 1 N—S(O)— and ROC(O)—, wherein R and R 1  are each independently selected from the group consisting of hydrogen, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted arylalkyl group, an optionally substituted heteroarylalkyl group and an optionally substituted alkyl group.    
     
     
         24 . The protease modulator of  claim 23 , wherein said modulator has the formula  
       
         
           
           
               
               
           
         
         wherein the ring ‘A’ is a member selected from the group consisting of a five- or a six-membered optionally substituted cycloalkyl group, optionally substituted aryl group and an optionally substituted heteroaryl group, wherein said heteroaryl group has from 1 to 3 heteroatoms selected from the group consisting of optionally substituted N, O, and S; and  
         z is 0 or 1;  
         L is selected from the group consisting of alkylene optionally interrupted by a heteroatom and S;  
         t is 0 or 1;  
         q is an integer from 0 to about 3; and  
         y is an integer from 1 to about 12 wherein each P 2  can be the same or different.  
       
     
     
         25 . The protease modulator of  claim 23 , wherein said modulator has the formula  
       
         
           
           
               
               
           
         
         wherein:  
         the ring ‘A’ is a member selected from the group consisting of a five- or a six-membered optionally substituted cycloalkyl group, optionally substituted aryl group and an optionally substituted heteroaryl group, wherein said heteroaryl group has from 1 to 3 heteroatoms selected from the group consisting of N, O, and S;  
         each P 2  may be the same or a different amino acid residue;  
         y is an integer of 1 to about 3;  
         G is carbon and n is 1; or alternatively,  
         G is sulfur and n is 0, 1 or 2;  
         Y is a heteroatom selected from the group consisting of optionally substituted N and O;  
         m is 0 or 1; and  
         R 4  is an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted arylalkyl group, an optionally substituted heteroarylalkyl group and an optionally substituted alkyl group.  
       
     
     
         26 . The protease modulator of  claim 25 , wherein said modulator has the formula  
       
         
           
           
               
               
           
         
         wherein:  
         X is a heteroatom selected from the group consisting of optionally substituted N, S and O;  
         each P 2  may be the same or different amino acid residue;  
         y is an integer of 1 to about 3;  
         G is carbon and n is 1; or alternatively,  
         G is sulfur and n is 0, 1 or 2;  
         Y is a heteroatom selected from the group consisting of optionally substituted N and O;  
         m is 0 or 1; and  
         R 4  is an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted arylalkyl group, an optionally substituted heteroarylalkyl group and an optionally substituted alkyl group.  
       
     
     
         27 . A method for modulating a protease, said method comprising: 
 contacting said protease with a compound having the formula:   P 1 —(P 2 ) y —P 4   Ia   wherein:    P 1  is an arginine surrogate;    P 2  is an amino acid residue;    y is an integer from 1 to about 12 wherein each P 2  can be the same or different; and    P 4  is a member selected from the group consisting of R—, RC(O)—, RR 1 NC(O)—, RSO 2 —, RR 1 N—SO 2 —, RS(O)—, RR 1 N—S(O)— and ROC(O)—, wherein R and R 1  are each independently selected from the group consisting of hydrogen, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted arylalkyl group, an optionally substituted heteroarylalkyl group, an optionally substituted heteroarylaryl group, an optionally substituted cycloalkyl group, an optionally substituted alkoxy group and an optionally substituted alkyl group, thereby modulating said protease.    
     
     
         28 . The method for modulating a protease of  claim 27 , wherein said protease is a serine protease.  
     
     
         29 . The method for modulating a protease of  claim 28 , wherein said serine protease is a Type II membrane bound protease.  
     
     
         30 . An amidine derivative composition, said amidine derivative composition comprising: 
 a) an amidine derivative attached directly to a solid support having the formula:                          wherein X is a heteroatom selected from the group consisting of optionally substituted N, S and O; and    b) a solid support